Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells

Chronic myeloid leukaemia (CML) is maintained by a rare population of tyrosine kinase inhibitor (TKI)-insensitive malignant stem cells. Our long-term aim is to find a BcrAbl-independent drug that can be combined with a TKI to improve overall disease response in chronic-phase CML. Omacetaxine mepesuccinate, a first in class cetaxine, has been evaluated by clinical trials in TKI-insensitive/resistant CML. Omacetaxine inhibits synthesis of anti-apoptotic proteins of the Bcl-2 family, including (myeloid cell leukaemia) Mcl-1, leading to cell death. Omacetaxine effectively induced apoptosis in primary CML stem cells (CD34<sup>+</sup>38<sup>lo</sup>) by downregulation of Mcl-1 protein. In contrast to our previous findings with TKIs, omacetaxine did not accumulate undivided cells <i>in vitro</i>. Furthermore, the functionality of surviving stem cells following omacetaxine exposure was significantly reduced in a dose-dependant manner, as determined by colony forming cell and the more stringent long-term culture initiating cell colony assays. This stem cell-directed activity was not limited to CML stem cells as both normal and non-CML CD34<sup>+</sup> cells were sensitive to inhibition. Thus, although omacetaxine is not leukaemia stem cell specific, its ability to induce apoptosis of leukaemic stem cells distinguishes it from TKIs and creates the potential for a curative strategy for persistent disease

The population impact of herpes simplex virus type 2 (HSV-2) vaccination on the incidence of HSV-2, HIV and genital ulcer disease in South Africa: a mathematical modelling study

BACKGROUND: Evidence suggests HSV-2 infection increases HIV acquisition risk and HIV/HSV-2 coinfection increases transmission risk of both infections. We analysed the potential impact of HSV-2 vaccination in South Africa, a high HIV/HSV-2 prevalence setting. METHODS: We adapted a dynamic HIV transmission model for South Africa to incorporate HSV-2, including synergistic effects with HIV, to evaluate the impact of: (i) cohort vaccination of 9-year-olds with a prophylactic vaccine that reduces HSV-2 susceptibility; (ii) vaccination of symptomatically HSV-2-infected individuals with a therapeutic vaccine that reduces HSV shedding. FINDINGS: An 80% efficacious prophylactic vaccine offering lifetime protection with 80% uptake could reduce HSV-2 and HIV incidence by 84.1% (95% Credibility Interval: 81.2-86.0) and 65.4% (56.5-71.6) after 40 years, respectively. This reduces to 57.4% (53.6-60.7) and 42.1% (34.1-48.1) if efficacy is 50%, 56.1% (53.4-58.3) and 41.5% (34.2-46.9) if uptake is 40%, and 29.4% (26.0-31.9) and 24.4% (19.0-28.7) if protection lasts 10 years. An 80% efficacious therapeutic vaccine offering lifetime protection with 40% coverage among symptomatic individuals could reduce HSV-2 and HIV incidence by 29.6% (21.8-40.9) and 26.4% (18.5-23.2) after 40 years, respectively. This reduces to 18.8% (13.7-26.4) and 16.9% (11.7-25.3) if efficacy is 50%, 9.7% (7.0-14.0) and 8.6% (5.8-13.4) if coverage is 20%, and 5.4% (3.8-8.0) and 5.5% (3.7-8.6) if protection lasts 2 years. INTERPRETATION: Prophylactic and therapeutic vaccines offer promising approaches for reducing HSV-2 burden and could have important impact on HIV in South Africa and other high prevalence settings. FUNDING: WHO, NIAID

Interventional suite and equipment management: cradle to grave

The acquisition process for interventional equipment and the care that this equipment receives constitute a comprehensive quality improvement program. This program strives to (a) achieve the production of good image quality that meets clinical needs, (b) reduce radiation doses to the patient and personnel to their lowest possible levels, and (c) provide overall good patient care at reduced cost. Interventional imaging equipment is only as effective and efficient as its supporting facility. The acquisition process of interventional equipment and the development of its environment demand a clinical project leader who can effectively coordinate the efforts of the many professionals who must communicate and work effectively on this type of project. The clinical project leader needs to understand (a) clinical needs of the end users, (b) how to justify the cost of the project, (c) the technical needs of the imaging and all associated equipment, (d) building and construction limitations, (e) how to effectively read construction drawings, and (f) how to negotiate and contract the imaging equipment from the appropriate vendor. After the initial commissioning of the equipment, it must not be forgotten. The capabilities designed into the imaging device can be properly utilized only by well-trained operators and staff who were initially properly trained and receive ongoing training concerning the latest clinical techniques throughout the equipment’s lifetime. A comprehensive, ongoing maintenance and repair program is paramount to reducing costly downtime of the imaging device. A planned periodic maintenance program can identify and eliminate problems with the imaging device before these problems negatively impact patient care

Survey of the quality of experimental design, statistical analysis and reporting of research using animals

For scientific, ethical and economic reasons, experiments involving animals should be appropriately designed, correctly analysed and transparently reported. This increases the scientific validity of the results, and maximises the knowledge gained from each experiment. A minimum amount of relevant information must be included in scientific publications to ensure that the methods and results of a study can be reviewed, analysed and repeated. Omitting essential information can raise scientific and ethical concerns. We report the findings of a systematic survey of reporting, experimental design and statistical analysis in published biomedical research using laboratory animals. Medline and EMBASE were searched for studies reporting research on live rats, mice and non-human primates carried out in UK and US publicly funded research establishments. Detailed information was collected from 271 publications, about the objective or hypothesis of the study, the number, sex, age and/or weight of animals used, and experimental and statistical methods. Only 59% of the studies stated the hypothesis or objective of the study and the number and characteristics of the animals used. Appropriate and efficient experimental design is a critical component of high-quality science. Most of the papers surveyed did not use randomisation (87%) or blinding (86%), to reduce bias in animal selection and outcome assessment. Only 70% of the publications that used statistical methods described their methods and presented the results with a measure of error or variability. This survey has identified a number of issues that need to be addressed in order to improve experimental design and reporting in publications describing research using animals. Scientific publication is a powerful and important source of information; the authors of scientific publications therefore have a responsibility to describe their methods and results comprehensively, accurately and transparently, and peer reviewers and journal editors share the responsibility to ensure that published studies fulfil these criteria

A temporal dimension to the influence of pollen rewards on bee behaviour and fecundity in Aloe tenuior

The net effect of pollen production on fecundity in plants can range from negative – when self-pollen interferes with fecundity due to incompatibility mechanisms, to positive – when pollen availability is associated with increased pollinator visitation and fecundity due to its utilization as a reward. We investigated the responses of bees to pollen and nectar rewards, and the effects of these rewards on pollen deposition and fecundity in the hermaphroditic succulent shrub Aloe tenuior. Self-pollinated plants failed to set fruit, but their ovules were regularly penetrated by self-pollen tubes, which uniformly failed to develop into seeds as expected from ovarian self-incompatibility (or strong early inbreeding depression). Bees consistently foraged for pollen during the morning and early afternoon, but switched to nectar in the late afternoon. As a consequence of this differential foraging, we were able to test the relative contribution to fecundity of pollen- versus nectar-collecting flower visitors. We exposed emasculated and intact flowers in either the morning or late afternoon to foraging bees and showed that emasculation reduced pollen deposition by insects in the morning, but had little effect in the afternoon. Despite the potential for self-pollination to result in ovule discounting due to late-acting self-sterility, fecundity was severely reduced in artificially emasculated plants. Although there were temporal fluctuations in reward preference, most bee visits were for pollen rewards. Therefore the benefit of providing pollen that is accessible to bee foragers outweighs any potential costs to fitness in terms of gender interference in this species

Gamma (γ) tocopherol upregulates peroxisome proliferator activated receptor (PPAR) gamma (γ) expression in SW 480 human colon cancer cell lines

BACKGROUND: Tocopherols are lipid soluble antioxidants that exist as eight structurally different isoforms. The intake of γ-tocopherol is higher than α-tocopherol in the average US diet. The clinical results of the effects of vitamin E as a cancer preventive agent have been inconsistent. All published clinical trials with vitamin E have used α-tocopherol. Recent epidemiological, experimental and molecular studies suggest that γ-tocopherol may be a more potent chemopreventive form of vitamin E compared to the more-studied α-tocopherol. γ-Tocopherol exhibits differences in its ability to detoxify nitrogen dioxide, growth inhibitory effects on selected cancer cell lines, inhibition of neoplastic transformation in embryonic fibroblasts, and inhibition of cyclooxygenase-2 (COX-2) activity in macrophages and epithelial cells. Peroxisome proliferator activator receptor γ (PPARγ) is a promising molecular target for colon cancer prevention. Upregulation of PPARγ activity is anticarcinogenic through its effects on downstream genes that affect cellular proliferation and apoptosis. The thiazolidine class of drugs are powerful PPARγ ligands. Vitamin E has structural similarity to the thiazolidine, troglitazone. In this investigation, we tested the effects of both α and γ tocopherol on the expression of PPARγ mRNA and protein in SW 480 colon cancer cell lines. We also measured the intracellular concentrations of vitamin E in SW 480 colon cancer cell lines. RESULTS: We have discovered that the α and γ isoforms of vitamin E upregulate PPARγ mRNA and protein expression in the SW480 colon cancer cell lines. γ-Tocopherol is a better modulator of PPARγ expression than α-tocopherol at the concentrations tested. Intracellular concentrations increased as the vitamin E concentration added to the media was increased. Further, γ-tocopherol-treated cells have higher intracellular tocopherol concentrations than those treated with the same concentrations of α-tocopherol. CONCLUSION: Our data suggest that both α and γ tocopherol can upregulate the expression of PPARγ which is considered an important molecular target for colon cancer chemoprevention. We show that the expression of PPARγ mRNA and protein are increased and these effects are more pronounced with γ-tocopherol. γ-Tocopherol's ability to upregulate PPARγ expression and achieve higher intracellular concentrations in the colonic tissue may be relevant to colon cancer prevention. We also show that the intracellular concentrations of γ-tocopherol are several fold higher than α-tocopherol. Further work on other colon cancer cell lines are required to quantitate differences in the ability of these forms of vitamin E to induce apoptosis, suppress cell proliferation and act as PPAR ligands as well as determine their effects in conjunction with other chemopreventive agents. Upregulation of PPARγ by the tocopherols and in particular by γ-tocopherol may have relevance not only to cancer prevention but also to the management of inflammatory and cardiovascular disorders

Mitigating the impact of Bats in historic churches: The response of Natterer's Bats Myotis nattereri to artificial roosts and deterrence

© 2016 Zeale et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Bats frequently roost in historic churches, and these colonies are of considerable conservation value. Inside churches, bat droppings and urine can cause damage to the historic fabric of the building and to items of cultural significance. In extreme cases, large quantities of droppings can restrict the use of a church for worship and/or other community functions. In the United Kingdom, bats and their roosts are protected by law, and striking a balance between conserving the natural and cultural heritage can be a significant challenge. We investigated mitigation strategies that could be employed in churches and other historic buildings to alleviate problems caused by bats without adversely affecting their welfare or conservation status. We used a combination of artificial roost provision and deterrence at churches in Norfolk, England, where significant maternity colonies of Natterer's bats Myotis nattereri damage church features. Radio-tracking data and population modelling showed that excluding M. nattereri from churches is likely to have a negative impact on their welfare and conservation status, but that judicious use of deterrents, especially high intensity ultrasound, can mitigate problems caused by bats. We show that deterrence can be used to move bats humanely from specific roosting sites within a church and limit the spread of droppings and urine so that problems to congregations and damage to cultural heritage can be much reduced. In addition, construction of bespoke roost spaces within churches can allow bats to continue to roost within the fabric of the building without flying in the church interior. We highlight that deterrence has the potential to cause serious harm toM. nattereri populations if not used judiciously, and so the effects of deterrents will need careful monitoring, and their use needs strict regulation

Comparative effects of RRR-alpha- and RRR-gamma-tocopherol on proliferation and apoptosis in human colon cancer cell lines

BACKGROUND: Mediterranean societies, with diets rich in vitamin E isoforms, have a lower risk for colon cancer than those of northern Europe and the Americas. Vitamin E rich diets may neutralize free radicals generated by fecal bacteria in the gut and prevent DNA damage, but signal transduction activities can occur independent of the antioxidant function. The term vitamin E represents eight structurally related compounds, each differing in their potency and mechanisms of chemoprevention. The RRR-γ-tocopherol isoform is found primarily in the US diet, while RRR-α-tocopherol is highest in the plasma. METHODS: The effectiveness of RRR-α- and RRR-γ-tocopherol at inhibiting cell growth and inducing apoptosis in colon cancer cell lines with varying molecular characteristics (SW480, HCT-15, HCT-116 and HT-29) and primary colon cells (CCD-112CoN, nontransformed normal phenotype) was studied. Colon cells were treated with and without RRR-α- or RRR-γ-tocopherol using varying tocopherol concentrations and time intervals. Cell proliferation and apoptosis were measured using the trypan blue assay, annexin V staining, DNA laddering and caspase activation. RESULTS: Treatment with RRR-γ-tocopherol resulted in significant cell death for all cancer cell lines tested, while RRR-α-tocopherol did not. Further, RRR-γ-tocopherol treatment showed no cytotoxicity to normal colon cells CCD-112CoN at the highest concentration and time point tested. RRR-γ-tocopherol treatment resulted in cleavage of PARP, caspase 3, 7, and 8, but not caspase 9. Differences in the percentage cell death and apoptosis were observed in different cell lines suggesting that molecular differences in these cell lines may influence the ability of RRR-γ-tocopherol to induce cell death. CONCLUSION: This is the first study to demonstrate that multiple colon cancer cell lines containing varying genetic alterations will under go growth reduction and apoptosis in the presence of RRR-γ-tocopherol without damage to normal colon cells. The amount growth reduction was dependent upon the molecular signatures of the cell lines. Since RRR-γ-tocopherol is effective at inhibition of cell proliferation at both physiological and pharmacological concentrations dietary RRR-γ-tocopherol may be chemopreventive, while pharmacological concentrations of RRR-γ-tocopherol may aid chemotherapy without toxic effects to normal cells demonstrated by most chemotherapeutic agents

Moderation in management research: What, why, when and how.

Many theories in management, psychology, and other disciplines rely on moderating variables: those which affect the strength or nature of the relationship between two other variables. Despite the near-ubiquitous nature of such effects, the methods for testing and interpreting them are not always well understood. This article introduces the concept of moderation and describes how moderator effects are tested and interpreted for a series of model types, beginning with straightforward two-way interactions with Normal outcomes, moving to three-way and curvilinear interactions, and then to models with non-Normal outcomes including binary logistic regression and Poisson regression. In particular, methods of interpreting and probing these latter model types, such as simple slope analysis and slope difference tests, are described. It then gives answers to twelve frequently asked questions about testing and interpreting moderator effects

Radio emission from Supernova Remnants

The explosion of a supernova releases almost instantaneously about 10^51 ergs of mechanic energy, changing irreversibly the physical and chemical properties of large regions in the galaxies. The stellar ejecta, the nebula resulting from the powerful shock waves, and sometimes a compact stellar remnant, constitute a supernova remnant (SNR). They can radiate their energy across the whole electromagnetic spectrum, but the great majority are radio sources. Almost 70 years after the first detection of radio emission coming from a SNR, great progress has been achieved in the comprehension of their physical characteristics and evolution. We review the present knowledge of different aspects of radio remnants, focusing on sources of the Milky Way and the Magellanic Clouds, where the SNRs can be spatially resolved. We present a brief overview of theoretical background, analyze morphology and polarization properties, and review and critical discuss different methods applied to determine the radio spectrum and distances. The consequences of the interaction between the SNR shocks and the surrounding medium are examined, including the question of whether SNRs can trigger the formation of new stars. Cases of multispectral comparison are presented. A section is devoted to reviewing recent results of radio SNRs in the Magellanic Clouds, with particular emphasis on the radio properties of SN 1987A, an ideal laboratory to investigate dynamical evolution of an SNR in near real time. The review concludes with a summary of issues on radio SNRs that deserve further study, and analyzing the prospects for future research with the latest generation radio telescopes.Comment: Revised version. 48 pages, 15 figure